Cosmetic and pharmaceutical compositions containing naphthalenol derivatives

ABSTRACT

A 5,6,7,8-tetrahydro-1-naphthalenol derivative of the formula ##STR1## wherein R 1 , R 2 , R 3  and R 4  represent lower alkyl, 
     R 5  and R 6  represent hydrogen or lower alkyl, 
     R represents hydrogen, C 1  -C 18  alkyl, C 2  -C 18  alkyl substituted by one or more hydroxyl groups, C 3  -C 18  alkenyl, C 2  -C 18  acyl, benzyl, benzoyl, carboxyl and carboxylic salts of an alkali or alkaline earth metal or of an organic amine. 
     The derivative is useful as an antioxidant in cosmetic compositions and in pharmaceutical compositions for the preventive treatment of cutaneous inflammations and allergies or certain forms of cancer.

This is a division of application Ser. No. 07/535,202, filed Jun. 8,1990 now U.S. Pat. No. 5,043,482.

The present invention relates to new derivatives of5,6,7,8-tetrahydro-1-naphthalenol, a process for their preparation andtheir use as antioxidants in cosmetic compositions and in pharmaceuticalcompositions for the preventative treatment of cutaneous inflammationsand allergies or certain forms of cancer.

The new derivatives of 5,6,7,8-tetrahydro-1-naphthalenol, in accordancewith the present invention, are considered to exhibit in a surprisingfashion excellent antioxidant properties vis-a-vis the peroxidation ofpolyunsaturated lipids and also vis-a-vis substances susceptible ofundergoing to thermo or photo-induced oxidation reactions (such asprotein, sugars, pigments, vitamins, polymers and the like).

Now, it is known that the peroxidation of lipids implies the formationof intermediary free radicals which damage cellular membranes composedof among others, phospholipids and are responsible principally for thephenomenon of skin ageing (A. L. Tappel in "Federation Proceedings",Vol. 32, No. 8, August, 1973).

Because of their antioxidant properties, the new derivatives of5,6,7,8-tetrahydro-1-naphthalenol of the present invention provide animproved means for combatting premature ageing of the skin caused byperoxidation of cutaneous lipids.

They also assure a better preservation of cosmetic or pharmaceuticalcompositions containing an oily phase by avoiding the rancidity ofunsaturated lipids which are present therein and which can be of animalorigin such as lanolin, cetin (spermaceti), beeswax, perhydrosqualeneand turtle oil, or of vegetable origin such as olive oil, ricin oil,corn oil, sweet almond oil, avocado oil, karite oil, turnsol oil, soyoil, peanut oil, copra oil, hydrogenated palm oil, essential fatty acidssuch as vitamin F and certain essential acids present in perfumes suchas lemon oil or lavender oil.

These new derivatives also permit the avoidance of the oxidativedegradation of active compounds contained in pharmaceutical compositions(vitamin A, carotenoids and the like).

In a quite surprising manner, it has also been noted that the5,6,7,8-tetrahydro-1-naphthalenol derivatives, in accordance with thepresent invention, can also be employed in the treatment of cutaneousinflammations and allergies and also in the prevention of certaincancers.

In addition to their good antioxidant properties, the new derivatives of5,6,7,8-tetrahydro-1-naphthalenol exhibit excellent liposolublecharacteristics as well as very good thermal stability. Moreover, theyalso exhibit the advantage of being non-toxic or non-irritating and haveperfect innocuousness vis-a-vis the skin.

These new derivatives of 5,6,7,8-tetrahydro-1-naphthalenol can berepresented by the following general formula ##STR2## wherein

R₁, R₂, R₃ and R₄ represent lower alkyl,

R₅ and R₆ represent hydrogen or lower alkyl,

R represents hydrogen, C₁ -C₁₈ alkyl, C₁ -C₁₈ alkyl substituted by oneor more hydroxy groups, C₃ -C₁₈ alkenyl, C₂ -C₁₈ acyl, benzyl, benzoyl,carboxyl and carboxylic salts of an alkali or alkaline earth metal or ofan organic amine.

By lower alkyl is meant a radical having 1-6 carbon atoms.

Representative lower alkyl radicals and those having up to 18 carbonatoms, include principally methyl, ethyl, isopropyl, isobutyl, butyl,tert. butyl, 2-ethylhexyl, isooctyl, dodecyl, hexadecyl and octadecylradicals.

Representative C₁ -C₁₈ alkyl radicals substituted by one or morehydroxyl groups, include principally the 1-hydroxyethyl,2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxybutyl, 1-hydroxyhexyl,1-hydroxy-1-ethylhexyl or 2,3-dihydroxypropyl radicals.

Representative C₃ -C₁₈ alkenyl radicals include principally propenyl,butenyl, hexenyl, octenyl, dodecenyl and octadecenyl radicals.

Representative C₂ -C₁₈ acyl radicals include principally acetyl,propionyl, butyryl, isobutyryl, hexanoyl, octanoyl, dodecanoyl andoctadecanoyl radicals.

When R is benzyl or benzoyl it can be represented by the followingformula ##STR3## wherein Z represents --CO--, --CHOH-- or --CH₂ -- and

Y represents hydrogen, halogen and preferably chlorine, alkoxy andpreferably methoxy or trifluoromethyl.

The salts of the compounds of formula I when R=--COOH are preferablysalts of sodium, potassium, magnesium or an organic amine such astriethanolamine.

Representative particularly preferred derivatives of5,6,7,8-tetrahydro-1-naphthalenol corresponding to general formula Iinclude particularly the following:

4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,

2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,

2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,

2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,

2-(2-propenyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,

1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid,

1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalene,

2-benzoyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenoland

2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol.

The present invention also relates to a process for preparing thecompounds of formula I such as defined above.

This process can be represented by the following reaction scheme##STR4##

It consists essentially in reacting a 2,5-dichloro alkane (1) with a4-alkoxy phenol (2) (R'=H) or a 1,4-dialkoxy benzene (2) (R'=alkyl) inan organic solvent such as nitromethane or a dichloro solvent such as1,2-dichloroethane or methylene chloride, but preferably1,2-dichloroethane, in the presence of a Lewis acid, preferably aluminumchloride. This reaction is, however, only possible when the nature ofthe substituents R and R₆ permit it.

When the initial reactant (2) is a 1,4-dialkoxy benzene, the1,4-dialkoxy derivative of formula (1') (R'=alkyl) is then submitted toa treatment in the presence of hydriodic or hydrobromic acid to producethe corresponding phenol (I') (R'=H).

In accordance with a preferred embodiment, the compounds of formula (I)in which R=H are obtained starting with compounds of formula (1')wherein R=H and this in accordance with the following reaction scheme:##STR5##

By acylation of the compound of formula (I') wherein R and R'=H using anacid halide or an acid anhydride in the presence of aluminum chloride,the ketone of formula (3) is obtained in a very good yield.

This ketone (3) can be reduced by sodium borohydride into thecorresponding alcohol in a solvent such as methanol or ethanol or in anether such as tetrahydrofuran or in a mixture of these solvents.

The ketone (3) can also be transformed into a tertiary alcohol (4) bythe direct action of a magnesium alkyl halide under classic conditionsfor organo-magnesium reactions.

This tertiary alcohol (4) treated in an acid medium leads to thecorresponding alkene (5) in a good yield.

The compound of formula (I') wherein R=H and R'=alkyl can be acylated bythe action of acetyl chloride in the presence of aluminum chloride so asto produce the ketone (6).

This can then be transformed by oxidation with sodium hypochlorite orhypobromite into the corresponding acid (7).

This acid (7) treated by hydriodic or hydrobromic acid in an organicacid such as acetic acid leads then to the acid (8).

According to the duration of the treatment with hydriodic or hydrobromicacid, this acid (8) must be purified because it contains either theremainder of the initial reactant (7), or a hydroquinone derivative(compound of formula 8 in which R₅ =H).

The present invention also relates to a cosmetic composition comprising,in a cosmetically acceptable support containing at least one fattyphase, an effective amount of at least one5,6,7,8-tetrahydro-1-naphthalenol derivative of formula (I) such asdefined above.

The cosmetic composition of the present invention can be employed asprotective composition of human skin or hair or as an anti-solacomposition.

In accordance with the invention the compound of formula (I) isgenerally present in an amount ranging from 0.05 to 10 weight percentrelative to the total weight of the cosmetic composition and preferablyfrom 0.1 to 5 weight percent.

In the compositions according to the present invention, the compound offormula (I) acts as an antioxidant agent. These compositions can becapillary compositions such as hair lacquers, hair setting lotions orhair treating or disentangling lotions, shampoos, coloring shampoos,hair dye compositions, makeup products such as nail enamels, skintreating creams and oils, foundations, lipsticks, compositions for thecare of the skin such as bath oils or creams as well as any othercosmetic composition capable of exhibiting, because of their components,oxidation stability problems during storage.

As has been stated above, the compounds of formula (I) also exhibit aninteresting pharmacologic activity in the field of the preventativetreatment of cutaneous inflammations and allergies. They can also beemployed in the prevention of certain cancers.

The present invention thus relates to a compound of formula (I) in itsuse as a medicine.

The present invention also relates to a pharmaceutical composition,containing an effective amount of at least one compound of formula (I)as an active ingredient in a non-toxic support or excipient.

The pharmaceutical composition conforming to the present invention canbe administered orally or topically.

When administered orally, the pharmaceutical composition can be providedin the form of tablets, gelules, lozenges, syrups, suspensions,solutions, emulsions and the like.

When administered topically, the pharmaceutical composition of thepresent invention can be provided in the form of ointments, creams,pomades, solutions, lotions, gels, sprays, suspensions and the like.

These medicinal compositions can contain inert or pharmacodynamicallyactive additives an principally hydrating agents, antibiotics, steroidalor non-steroidal anti-inflammatory agents, carotenoids or anti-psoriasicagents.

This composition can also contain flavor improving agents,preservatives, stabilizing agents, humidity regulating agents, pHregulating agents, osmotic pressure modifying agents, emulsifiers, localanesthetics, buffers and the like.

It can also be packaged in delay or progressive release forms.

The compound of formula (I) conforming to the present invention isgenerally present in the pharmaceutical compositions in an amountranging from 0.01 to 20 weight percent relative to the total weight ofthe composition and preferably from 0.1 to 5 weight percent.

In a therapeutic use, the treatment is determined by the practioner andcan vary according to the age, weight and patient response as well as tothe seriousness of the symptoms.

When the compounds of formula (I) are administered orally, the dosage isgenerally between 0.1 and 50 mg/kg/day and preferably between 0.2 to 20mg/kg/day. The duration of the treatment varies according to theseriousness of the symptoms and can extend between 1 and 25 weeks in acontinuous or discontinuous fashion.

The topically applied compositions contain preferably from 0.25 to 4weight percent of the compound of formula (I). As the support orexcipient of the pharmaceutical composition according to the presentinvention, any conventional non-toxic support or excipient can beemployed.

In order to illustrate the invention and without any limiting character,examples of the preparation of the compounds of formula (I) as well asexamples of the use of these compounds in the cosmetic andpharmaceutical fields are now given.

EXAMPLE I Preparation of4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol (a)2,5-dichloro-2,5-dimethyl hexane

A suspension of 14.6 g of 2,5-dimethyl-2,5-hexanediol in 150 cm³ ofconcentrated HCl is stirred, for 1 hour, at a temperature of about 5° C.The solid is then filtered, thoroughly washed with water and then driedat ambient temperature on potash and under reduced pressure. 16.5 g of2,5-dichloro-2,5-dimethyl hexane in the form of white crystals meltingat 65° C. are obtained.

(b) 4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

At a temperature between 0° and 5° C., under an inert atmosphere, 10.8 gof anhydrous aluminum chloride are added to a suspension of 49.7 g of4-hydroxy anisole and 73.2 g of 2,5-dichloro-2,5-dimethyl hexane,obtained in step (a) above, in 230 cm³ of 1,2-dichloroethane.

5 minutes after the introduction of the aluminum chloride, the mediumbecomes homogeneous and is progressively colored red-brown. This mixtureis then stirred for 5 hours at ambient temperature, at the end of whichtime the major portion of the initial reactant is transformed. 200 cm³of ice water are then added. The mixture is stirred for 1/4 hour, thenthe phase is decanted. The aqueous phase is extracted twice with 150 cm³of methylene chloride. The combined organic phases are washed withwater, dried on sodium sulfate and the solvent is evaporated underreduced pressure. The crude product is then recrystallized in hexane. 50g of 4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol areobtained in the form of white crystals having a melting point of 127° C.

    ______________________________________                                        Elemental analysis: C.sub.15 H.sub.22 O.sub.2                                 ______________________________________                                        Calc.:   C: 76.88   H: 9.36    O: 13.65                                       Found:   76.87      9.50       13.73                                          ______________________________________                                    

EXAMPLE II Preparation of2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

To a mixture, stirred under an inert atmosphere, at a temperaturebetween 0° C. and 5° C., of 20.4 g of4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,obtained in Example I, and 6.18 cm, of acetyl chloride in 80 cm, of1,2dichloroethane, there are added, by small portions, 17.4 g ofanhydrous aluminum chloride over a period of about 1/2 hour in a mannerso that the temperature does not exceed 5° C. At the end of theintroduction the mixture is again stirred for 1 hour at this temperatureand then for 1 hour at ambient temperature. The solution is then pouredinto 100 cm³ of ice water. At this stage an emulsion is obtained whichis extracted three times with 100 cm³ of methylene chloride. The organicphases are combined, washed with water until a neutral pH of the washwaters, dried on sodium sulfate and the solvent removed by evaporationunder a vacuum.

The resulting crude product is purified by silica gel chromatography.The anticipated acyl derivative is eluted with a 60/40 hexane/methylenechloride mixture. After evaporation of the eluant phases, thenrecrystallization in ethanol, 12 g of2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1naphthaleneare obtained in the form of light yellow needles having a melting pointof 90° C.

    ______________________________________                                        Elemental analysis: C.sub.17 H.sub.24 O.sub.3                                 ______________________________________                                        Calc.:   C: 73.88   H: 8.75    O: 17.37                                       Found:   73.87      8.84       17.20                                          ______________________________________                                    

In the last chromatography fractions a secondary product is entrainedwhich corresponds to an O-acylation. It is a question of1-acetoxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalenein the form of white crystals having a melting point of 90° C.

EXAMPLE III Preparation of2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthelenol

To a stirred solution at ambient temperature under inert atmosphere, of2.9 g of2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,obtained in Example II, in a mixture of 40 cm³ of methanol and 5 cm³ oftetrahydrofuran, there are added over a period of about 20 minutes, bysmall portions, 1.5 g of sodium borohydride. After the end of theintroduction the solution is again stirred for 1 hour at ambienttemperature, then cooled to about 5° C., the temperature at which thereare introduced, with stirring, 100 cm³ of water. This mixture isacidified, with stirring, by the addition of 45 cm³ of 1N HCl, thenextracted 3 times with 50 cm³ of ethyl ether. The ether phases arecombined, washed with water, dried on sodium sulfate and thenconcentrated to dryness.

3 g of a yellow solid are obtained and then purified by passage througha silica gel column that is eluted with methylene chloride.

After evaporation of the eluant, 2.4 g of a light yellow powder having amelting point of 99° C. are obtained.

    ______________________________________                                        Elemental analysis: C.sub.17 H.sub.26 O.sub.3                                 ______________________________________                                        Calculated:                                                                             C: 73.35    H: 9.41   O: 17.24                                      Found:    73.25       9.40      17.44                                         ______________________________________                                    

EXAMPLE IV Preparation of2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

To a stirred solution, at -25° C. under an inert atmosphere, of 7.3 g of2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalene,obtained in Example II, in 120 cm³ of anhydrous ethyl ether, there areadded over a period of about 1/4 hour, 19 cm³ of a 3M solution of methylmagnesium bromide in ether.

The formation of a yellow precipitate is observed and the temperature atthe end of the introduction of the magnesium is -15° C. Stirring ismaintained for an additional 1/2 hour at this temperature, then for 1hour at 10° C. The major portion of the initial reactant is thustransformed. The mixture is hydrolyzed at 0° C. by the addition of 25cm³ of water, then 60 cm³ of 1N HCl. The ether phase is decanted and theaqueous phase extracted twice with 100 cm³ of ethyl ether.

The combined organic phases are washed with water, dried on sodiumsulfate and concentrated. The resulting white solid is recrystallized inhexane in the presence of a trace of acetone. 7 g of2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol are obtained in the form of white crystalshaving a melting point of 140° C.

    ______________________________________                                        Elemental analysis: C.sub.18 H.sub.28 O.sub.3                                 ______________________________________                                        Calculated:                                                                             C: 73.93    H: 9.65   O: 16.41                                      Found:    74.02       9.62      16.30                                         ______________________________________                                    

EXAMPLE V Preparation of2-(2-propenyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

At ambient temperature, 30 cm³ of a 50% solution of sulfuric acid areslowly added to 2 g of2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,obtained in Example IV, dissolved in 30 cm³ of methylene chloride. Themixture is left to stand overnight at ambient temperature. The methylenechloride phase is decanted, washed with water until neutral pH of thewash waters, dried on sodium sulfate and then concentrated. The expectedproduct is purified by passage through a silica gel chromatographycolumn. It is eluted by a 50:50 mixture of methylene chloride/hexane.

After evaporation of the eluant, 1.3 g of a light yellow liquid, whoseNMR ¹ H 80 MHz spectrum corresponds to the expected structure, areobtained.

EXAMPLE VI Preparation of1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalenecarboxylic acid (a) 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene

To a solution, stirred at 0° C. under an inert atmosphere, of 165.5 g of1,4-dimethoxybenzene and 218.7 g of 2,5dichloro-2,5 -dimethyl hexane,obtained in Example I(a), in 750 cm³ of anhydrous 1,2-dichloroethane,there are added, all at once, 31.9 g of powdered anhydrous aluminumchloride. The mixture is stirred for 1 hour at ambient temperature andthen left to stand overnight. The next day after 4 hours stirring atthis temperature, 600 cm³ of ice water are added. The organic phase isdecanted and the aqueous phase is extracted three time with 400 cm³ ofmethylene chloride. The organic phases are combined, washed with wateruntil neutral pH of the wash waters, then dried on sodium sulfate andconcentrated. The resulting crude product is treated with animalcharcoal in boiling ethanol, then recrystallized in this solvent. 195 gof 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene areobtained in the form of white needles having a melting point of 195° C.

(b) 2-acetyl-1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene

To a solution, stirred at a temperature of about -10° C., of 74. 4 g of1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene,obtained in step (a) above, and 21.3 cm³ of acetyl chloride in 380 cm³of 1,2-dichloroethane, there are added, in small portions, 48 g ofanhydrous aluminum chloride over a period of about 3/4 hour. After theend of the addition, the mixture is stirred for 1 hour 30 minutes at 0°C., and diluted by the addition of 700 cm³ ice water. The organic phaseis then decanted, washed several times with water until neutral pH ofthe wash waters and dried on sodium sulfate. After removal of thesolvent by distillation under a vacuum, the resulting crude product isrecrystallized in ethanol. 76 g of2-acetyl-1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene are obtained in the form of white needles having a meltingpoint of 97° C.

    ______________________________________                                        Elemental analysis: C.sub.18 H.sub.26 O.sub.3                                 ______________________________________                                        Calculated:                                                                             C: 74.45    H: 9.02   O: 16.53                                      Found:    74.42       8.99      16.62                                         ______________________________________                                    

(c) 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid

In a first stage a sodium hypobromite solution is prepared by slowlyadding 77 cm³ of bromine to a solution containing 192.7 g of soda in 890cm³ water cooled to between 0° C. and 5° C. The mixture is kept, withstirring, at 0° C.

In a second stage, this hypobromite solution is slowly added to astirred solution, cooled to about 5° C., of 43 g of2-acetyl-1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene, obtained in stage (b) above, in 500 cm³ of dioxane. Therate of introduction is such that the temperature does not exceed 15° C.The reaction mixture is then left to stand overnight, diluted with 300cm³ of water, then, at a temperature lower than 20° C., the excesssodium hypobromite is destroyed by the slow addition of a 25% aqueoussolution of sodium bisulfite. The expected acid is then precipitated byacidifying the mixture by the addition of 380 cm³ of 6N HCl. Theprecipitate is filtered, washed with water and dried under reducedpressure. 40.8 g of1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid are obtained in the form of a white solid having amelting point of 187° C.

    ______________________________________                                        Elemental analysis: C.sub.17 H.sub.24 O.sub.4                                 ______________________________________                                        Calculated:                                                                             C: 69.84    H: 8.27   O: 21.89                                      Found:    69.56       8.29      21.64                                         ______________________________________                                    

(d)1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid

To a stirred solution, at ambient temperature under an inert atmosphere,of 30 g of1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid, obtained above in stage (c), in 150 cm³ of acetic acid300 cm³ of a 57% solution of iodhydric acid are rapidly added. Themixture is then brought to reflux for 1/2 hour, then the temperature isadjusted towards 30° C., the temperature at which it is poured into 1250cm³ of ice water. The precipitate which forms is filtered, washedseveral times with water until neutral pH of the wash waters and thendried.

27 g of1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid containing a small amount of1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid are obtained.

This mixture is fractionated by chromatography on a silica gel column.The principal product is eluted with a 2/8/90 aceticacid/dioxane/toluene mixture. After evaporation of the eluant andrecrystallization in toluene 10 g of1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid are obtained in the form of white crystals having amelting point of 213° C.

    ______________________________________                                        Elemental analysis: C.sub.16 H.sub.22 O.sub.4                                 ______________________________________                                        Calculated:                                                                             C: 69.04    H: 7.97   O: 22.99                                      Found     69.14       8.01      23.08                                         ______________________________________                                    

In the following elution fractions,1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid is entrained. After evaporation of the eluant, 3 g ofbeige crystals having a melting point of 215° C. are obtained.

    ______________________________________                                        Elemental analysis: C.sub.15 H.sub.20 O.sub.4                                 ______________________________________                                        Calculated:                                                                             C: 68.16    H: 7.63   O: 24.21                                      Found     68.20       7.61      24.32                                         ______________________________________                                    

If it is desired to obtain this latter acid as the principal productthen the reaction mixture is maintained at least 3 hours under reflux.

EXAMPLE VII Preparation of1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene (a)5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,4-naphthoquinone

To a solution of 17.42 g (0.07 mole) of1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene,obtained in Example VIa, in 340 cm³ of dioxane, cooled to +5° C., thereare added, with stirring, 34.7 g (0.28 mole) of silver oxide, AgO(II),then rapidly drop-by-drop, 70 cm³ (0.42 mole) of 6N HNO₃.

Cooling is suspended and the reaction mixture is stirred until there isa total consumption of the silver oxide (10 to 15 minutes). 500 cm³ ofdichloromethane in 200 cm³ of water are then added.

The organic phase is separated by decanting, washed with 200 cm³ ofwater, dried on sodium sulfate and evaporated to dryness. The resultingred oil is chromatographed on silica gel using, as the eluant, a 60/40hexane/dichloromethane mixture.

After evaporation and drying 2.7 g of5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,4-naphthoquinone are obtainedin the form of a red oil.

The NMR ¹ H 80 MHz spectrum conforms to the expected structure.

    ______________________________________                                        Elemental analysis: C.sub.14 H.sub.18 O.sub.2                                 ______________________________________                                        Calculated:                                                                             C: 77.03    H: 8.31   O: 14.66                                      Found:    76.87       8.28      14.68                                         ______________________________________                                    

(b) 1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene

To a suspension of 40 mg (˜1 mole) of lithium aluminum hydride in 2 cm³of anhydrous ethyl ether, stirred under an inert atmosphere and cooledto +5° C., there is slowly added a solution of 0.22 g (˜1 mole) of5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,4-naphthoquinone, obtained instep (a) above, in 2 cm³ of anhydrous ethyl ether. After 30 minutes ofstirring water is slowly added to destroy excess hydride, then 30 cm³ ofethyl ether and finally a few drops of 1N Hcl up to an acid pH.

The ether phase is separated, washed with water, dried on sodium sulfateand evaporated to dryness under an inert atmosphere.

0.2 g of 1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene is obtained in the form of a beige solid having a meltingpoint of 114° C.

The NMR ¹ H CDCl₃ 80 MHz spectrum under an inert atmosphere conforms tothe expected structure (δ=1.25 ppm, s, 12H, HCH₃ ; δ=164 ppm, s, 4H,2CH₂ ; δ=6.90 ppm, 2H aromatics).

When the solution in deutrochloroform is not preserved under an inertgas there is observed the presence of stray signals corresponding to thequinone (δ=1.29 ppm, s, CH₃ :δ=1.51 ppm, s, CH₂ ; H quinonics). After 5hours in solution the quinone is no longer observed.

    ______________________________________                                        Elemental analysis: C.sub.14 H.sub.20 O.sub.2                                 ______________________________________                                        Calculated:                                                                             C: 76.32    H: 9.15   O: 14.52                                      Found:    76.37       8.98      14.60                                         ______________________________________                                    

EXAMPLE VIII Preparation of2-benzoyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

To a solution cooled to +5° C. of 23.44 g (0.1 mole) of4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,obtained in Example I, in 400 cm³ of anhydrous 1,2-dichloroethane and11.7 cm³ (14.06 g=0.1 mole) of benzoyl chloride, there are added, byportions, 16 g (0.12 mole) of anhydrous aluminum chloride over a periodof about 30 minutes.

At the end of the introduction, the mixture is stirred for 2 hours whilepermitting the temperature to return to ambient temperature.

The solution is then poured into 250 cm³ of ice water. The aqueous phaseis separated by decanting and re-extracted 3 times with 200 cm³ ofdichloromethane. The organic phases are combined, washed with wateruntil a neutral pH of the wash waters, dried on sodium sulfate andevaporated to dryness under reduced pressure.

The resulting crude product (32.2 g) is purified by chromatography onsilica gel with a 90/10 heptane/dichloromethane eluant.

After evaporation of the eluant phases, then drying under a vacuum at60° C., 19.95 g of2-benzoyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenolare obtained in the form of a yellow solid having a melting point of 85°C.

The NMR ¹ H 80 MHz spectrum conforms to the expected structure.

EXAMPLE IX Preparation of2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol

To a suspension of 30 mmoles of sodium hydride in 5 cm³ of toluene,stirred at ambient temperature under an inert atmosphere, there isslowly added a solution of 7.22 g (30 mmoles) of4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,obtained in Example I, in about 20 cm³ of toluene while maintaining thetemperature at 20° C. The resulting solution is heated to reflux. 4.33 g(33.9 mmoles) of benzyl chloride are slowly introduced over a period ofabout 30 minutes. Reflux is maintained 5 hours. After cooling to ambienttemperature 40 cm³ of IN HCl are slowly added and the mixture is stirredfor 15 minutes. The two phases are separated by decanting. The aqueousphase is re-extracted twice with 200 cm³ of toluene. The organic phasesare combined, washed with water, dried on sodium sulfate andconcentrated under reduced pressure. The resulting oil is purified bysilica gel chromatography using a 90/10 heptane/dichloromethane mixtureas the eluant, followed by recrystallization in ethyl alcohol at 96° C.

After filtering and drying under a vacuum at 60° C. 2.2 g of2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenolare obtained in the form of a white solid having a melting point of 80°C.

The NMR ¹ H 250 MHz spectrum conforms to the expected structure.

    ______________________________________                                        Elemental analysis: C.sub.22 H.sub.28 O.sub.2                                 ______________________________________                                        Calculated:                                                                             C: 81.44    H: 8.70   O: 9.86                                       Found     81.48       8.63      10.03                                         ______________________________________                                    

EXAMPLES OF COMPOSITIONS Example A Gel

    ______________________________________                                        2-(1-hydroxyethyl)4-methoxy-5,5,8,8-                                                                      0.12 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  Carboxy vinyl polymer, sold by Goodrich                                                                   0.80 g                                            under the trade name "Carbopol 934"                                           Glycerine                   12.00 g                                           Ethanol                     15.00 g                                           Preservative                0.20 g                                            Perfume                     0.20 g                                            Triethanolamine, sufficient for pH = 5.3                                      Demineralized water, sufficient amount for                                                                100.00 g                                          ______________________________________                                    

Example B Oil

    ______________________________________                                        4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-                                                                    0.60 g                                            tetrahydro-1-naphthalenol                                                     Benzoate of C.sub.12 -C.sub.15 alcohols, sold by                                                          30.00 g                                           Finetex under the trade name "FINSOLV TN"                                     Stabilized, raffinated turnsole oil                                                                       20.00 g                                           Perfume                     1.00 g                                            Silicone oil, sold by Union Carbide                                                                       100.00 g                                          under the trade name "Volatile                                                silicone 7207", sufficient amount for                                         ______________________________________                                    

Example C Milk in the Form of a Water-in-Oil Emulsion

    ______________________________________                                        2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-                                                                 0.25 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  Benzylidene camphor         2.00 g                                            Mixture of fatty acid esters,                                                                             5.00 g                                            polyglycerolated esters and silicone                                          surfactants, sold by Goldschmidt                                              under the trade name "ABIL W SO 8"                                            White petrolatum            2.00 g                                            Beeswax                     2.50 g                                            Benzoate of C.sub.12 -C.sub.15 alcohols, sold by                                                          19.00 g                                           Finetex under the trade name "FINSOLV TN"                                     Glycerine                   5.00 g                                            Sodium chloride             2.00 g                                            Perfume                     0.40 g                                            Preservative                0.20 g                                            Demineralized water, sufficient amount for                                                                100.00 g                                          ______________________________________                                    

Example D Milk

    ______________________________________                                        2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-                                                                     1.50 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  2-ethylhexyl p-hydroxycinnamate,                                                                          3.50 g                                            sunscreen agent                                                               2-hydroxy-4-methoxy benzophenone,                                                                         1.00 g                                            sunscreen agent                                                               Cetyl alcohol               1.00 g                                            Oleocetyl alcohol having 30 moles of                                                                      5.00 g                                            ethylene oxide, sold by Henkel                                                under the trade name "MERGITAL OC 30"                                         Stearyl alcohol             4.00 g                                            1-hexadecanoyloxy-3-(2'-ethyl hexyl ether)-                                                               2.00 g                                            2-propanol                                                                    90/10 mixture of ketostearyl 2-ethyl                                                                      2.00 g                                            hexanoate and isopropyl myristate,                                            sold under the trade name "CERAMOLL"                                          by Creations Aromatiques                                                      Petrolatum oil              8.00 g                                            Propylene glycol            8.00 g                                            Preservative                0.20 g                                            Perfume                     0.40 g                                            Demineralized water, sufficent amount for                                                                 100.00 g                                          ______________________________________                                    

Example E Stick

    ______________________________________                                        4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-                                                                    1.00 g                                            tetrahydro-1-naphthalenol                                                     Ozokerite                   20.00 g                                           Beeswax                     7.00 g                                            Oleic alcohol               12.00 g                                           Hydrogenated lanolin        8.00 g                                            Lanolin oil                 8.00 g                                            Carnauba wax                1.00 g                                            Benzoate of C.sub.12 -C.sub.15 alcohols, sold by                                                          17.00 g                                           Finetex under the trade name "FINSOLV TN"                                     Octamethylcyclotetrasiloxane, sold by                                                                     3.00 g                                            Goldschmidt under the trade name "ABIL K4"                                    Petrolatum oil, sufficient amount for                                                                     100.00 g                                          ______________________________________                                    

Example F Cream in the Form of an Oil-in-Water Emulsion

    ______________________________________                                        2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-                                                                     0.50 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  (2-oxo-3-bornylidene)-4-methyl phenyl                                                                     4.00 g                                            trimethyl ammonium methyl sulfate                                             Sodium lactate              1.00 g                                            Keto-stearyl alcohol and oxyethylenated                                                                   7.50 g                                            fatty alcohols, sold by Sinnova                                               under the trade name "SINNOWAX 40"                                            Mixture of non self-emulsifiable glycerol                                                                 2.0 g                                             mono and distearate                                                           Cetyl alcohol               1.00 g                                            Myristic alcohol            0.60 g                                            Sorbitol, 70%               3.00 g                                            Isopropyl palmitate         10.00 g                                           Petrolatum oil              7.00 g                                            Preservative                0.20 g                                            Perfume                     0.60 g                                            Demineralized water, sufficient amount for                                                                100.00 g                                          Pharmaceutical Composition For Topical Application                            ______________________________________                                    

Example G Ointment

    ______________________________________                                        4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-                                                                    2.00 g                                            tetrahydro-1-naphthalenol                                                     Fluid petrolatum oil        9.10 g                                            Silica, sold by Degussa under the                                                                         9.20 g                                            trade name "AEROSIL 200"                                                      Isopropyl myristate, sufficient amount for                                                                100.00 g                                          ______________________________________                                    

In this example the active compound can be replaced by the same amountof2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol.

Example H Anionic Oil-in-Water Cream

    ______________________________________                                        2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-                                                                     3.00 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  Sodium dodecyl sulfate      0.80 g                                            Glycerol                    2.00 g                                            Stearyl alcohol             20.00 g                                           Triglycerides of capric/caprylic acids,                                                                   20.00 g                                           sold by Dynamit Nobel under the                                               trade name "MIGLYOL 812"                                                      Preservative, sufficient amount                                               Demineralized water, sufficient amount for                                                                100 g                                             ______________________________________                                    

In this example the active compound can be replaced by the same amountof2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol.

Example I Gel

    ______________________________________                                        2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-                                                                 1.00 g                                            tetramethyl-5,6,7,8-tetrahydro-1-                                             naphthalenol                                                                  Hydroxypropyl cellulose, sold by Hercules                                                                 2.00 g                                            under the trade name "KLUCEL HP"                                              Ethanol                     70.00 g                                           Water, sufficient amount for                                                                              100.00 g                                          ______________________________________                                    

In this example the active compound can be replaced by 0.5 g of2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol.

What is claimed is:
 1. A cosmetic composition for the protection ofhuman skin or hair comprising in a cosmetically acceptable supportcontaining at least one oily phase, at least one5,6,7,8-tetrahydro-1-naphthalenol derivative having the formula ##STR6##wherein R₁, R₂, R₃ and R₄ represent lower alkyl,R₅ and R₆ representhydrogen or lower alkyl, R represents hydrogen, C₁ -C₁₈ alkyl, C₂ -C₁₈alkyl substituted by one or more hydroxy groups, C₃ -C₁₈ alkenyl, C₂-C₁₈ acyl, benzyl, benzoyl, carboxyl and the carboxylic salts of analkali or alkaline earth metal or of an organic amine, said derivativebeing present in an amount effective to protect said human skin or hair.2. The cosmetic composition of claim 1 wherein said compound of formulaI is selected from the group consistingof4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(2-propenyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalenecarboxylic acid, 1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,2-benzoyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenoland2-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol.3. The cosmetic composition of claim 1 wherein said compound of formulaI is present in an amount ranging from 0.05 to 10 percent by weightbased on the total weight of said composition.
 4. A pharmaceuticalcomposition for avoiding peroxidation of cutaneous lipids comprising ina pharmaceutically acceptable support or excipient at least one5,6,7,8-tetrahydro-1-naphthalenol derivative having the formula ##STR7##wherein R₁, R₂, R₃ and R₄ represent lower alkyl,R₅ and R₆ representhydrogen or lower alkyl, R represents hydrogen, C₁ -C₁₈ alkyl, C₂ -C₁₈alkyl substituted by one or more hydroxy groups, C₃ -C₁₈ alkenyl, C₂-C₁₈ acyl, benzyl, benzoyl, carboxyl and the carboxylic salts of analkali or alkaline earth metal or of an organic amine, said derivativebeing present in an amount sufficient to avoid peroxidation of cutaneouslipids.
 5. The pharmaceutical composition of claim 4 wherein saidcompound of formula I is present in an amount ranging from 0.01 to 20percent by weight based on the total weight of said composition.
 6. Thepharmaceutical composition of claim 4 wherein said compound of formula Iis present in an amount ranging from 0.1 to 5 percent by weight based onthe total weight of said composition.
 7. The pharmaceutical compositionof claim 4 wherein said compound of formula I is selected from the groupconsistingof4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-acetyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(1-hydroxyethyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(2-hydroxy-2-propyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,2-(2-propenyl)-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1-naphthalenol,1-hydroxy-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalenecarboxylic acid, 1,4-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,2-benzoyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1naphthalenoland-benzyl-4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1naphthalenol8. A process for the preventative treatment of cutaneous inflammationsand allergies comprising applying to the skin in an amount effective toprevent cutaneous inflammations and allergies the pharmaceuticalcomposition of claim
 4. 9. A process for protecting a cosmeticcomposition against oxidation comprising incorporating into saidcosmetic composition at least one 5,6,7,8-tetrahydro-1-naphthalenolderivative having the formula ##STR8## wherein R₁, R₂, R₃ and R₄represent lower alkyl,R₅ and R₆ represent hydrogen or lower alkyl, Rrepresents hydrogen, C₁ -C₁₈ alkyl, C₂ -C₁₈ alkyl substituted by one ormore hydroxy groups, C₃ -C₁₈ alkenyl, C₂ -C₁₈ acyl, benzyl, benzoyl,carboxyl and the carboxylic salts of an alkali or alkaline earth metalor of an organic amine, in an amount effective to protect said cosmeticcomposition against oxidation.